This Project is focused on both Phase I and Phase II level clinical studies to evaluate the efficacy of selected herbal medicines to alter acute effects of alcohol or drugs of abuse, to modify alcohol- or drug-seeking behavior and to begin to explore the central mechanism of action of these products. In brief, a novel herbal preparation will be initially standardized, purified and characterized in Project 1 using cell based kappa receptor binding and functional assays and tested in a sequential animal model for efficacy in reducing drug or alcohol intake and discriminative stimulus properties in Project 2 and then a herbal remedy (or fractions) that remains efficacious through Project 1, and 2 will be studied clinically. However, as we have already identified two candidate products based on strong preclinical data, the first two years of this project will focus on studying the effects of the Chinese herbal remedy (NPI-028) on alcohol intoxication and drinking behavior. In subsequent years, we will either study the second Chinese herbal remedy (NPI-025) or if the drug discovery process in Projects 1 and 2 uncover a more promising candidate, the focus may shift to that product instead. Regardless of which products are selected, the protocols described in this project are easily adaptable and could be used to study any number of likely candidates. Using a multidisciplinary battery of subjective, physiologic and behavioral measures as well as plasma ethanol levels, we propose three main studies to systematically evaluate the efficacy of NPI-028 in altering alcohol's acute intoxicating effects and pharmacokinetic profile in adult male and female heavy drinkers. The effects of NPI-028 on ethanol drinking will be measured in a natural environment to simulate realistic drinking conditions. Finally, using brain imaging techniques, we will explore the possible mechanism of action of this herbal preparation using proton magnetic resonance spectroscopy (MRS) to determine whether pretreatment alters the amount of ethanol that actually enters the brain. We plan to continue and expand this experiment and, in addition, will measure changes in cerebral blood flow and cerebral vasculature using functional MR imaging (fMRI). The results of these studies will help define the role that herbal medicines may have in treating alcohol-related problems.